Processes and intermediates for quinine, quinidine, isomers and derivatives thereof

ABSTRACT

The preparation of quinine, quinidine, isomers and derivatives thereof from the correspondingly substituted 4-methylquinoline and 1-acyl(or 1-H)-3-vinyl(or lower alkyl)-4-piperidine acetic acid esters (or acetaldehyde) through alternative series of reaction steps which comprise, condensation, halogenation, deacylation, reduction, cyclization and hydroxylation, is described. Also described is the preparation of 1-acyl(or 1-H)-3vinyl-4-piperidineacetic acids and esters thereof and 1-acyl-3vinyl-4-piperidineacetaldehyde utilizing the corresponding 7acyldecahydro-2H-pyrido(3,4-d)azepin-2-one, prepared from 2-acyl1,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone. The end products are useful as antimalarial and antiarrhythmic agents.

Gutzwiller et al.

PROCESSES AND INTERMEDIATES FOR QUININE, QUINIDINE, ISOMERS ANDDERIVATIVES THEREOF Inventors: Juerg Albert Walter Gutzwiller,

Bettingen, Switzerland; Milan Radoje Uskokovic, Upper Montclair,

Assignee: Hoffmann-La Roche Inc., Nutley,

Filed: Aug. 1, 1973 Appl. No.: 384,781

Related US Application Data Division of Ser. No. 212,774, Dec. 27, 1971,Pat. No. 3,772,302, which is a continuation-in-part of Ser. No. 104,784,Jan. 7, 1971, abandoned, which is a continuation-in-part of Ser. No.837,354, June 27, I969, abandoned, which is a continuation-in-part ofSer. No. 74l,9l4, July 2, I968, abandoned.

U.S. Cl 260/288 R Int. Cl C07d 33/50 Field of Search 260/288 R l Mar.25, 1975 Primary Examiner-Donald G. Daus Assistant Examiner-David E.Wheeler Attorney, Agent, or Firm-Samuel L. Welt; Bernard S. Leon;William G. lsgro 57 ABSTRACT The preparation of quinine, quinidine,isomers and de-' rivatives thereof from the correspondingly substituted4-methylquinoline and l-acyl(or l-H)-3-vinyl(or loweralkyl)-4-piperidine acetic acid esters (or acetaldehyde) throughalternative series of reaction steps which comprise, condensation,halogenation, deacylation, reduction, cyclization and hydroxylation, isdescribed. Also described is the preparation of l-acyl(orl-H)-3-vinyl-4-piperidineacetic acids and esters thereof andl-acyl-3-vinyl-4-piperidineacetaldehyde utilizing the corresponding7-acyldecahydro-2H- pyrido[3,4-d1azepin-2-one, prepared from 2-acyll,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone. The end products are usefulas antimalarial and antiarrhythmic agents.

1 Claim, N0 Drawings PROCESSES AND INTERMEDIATES FOR QUININE, QUINIDINE,ISOMERS AND DERIVATIVES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONSThis is a division, of application Ser. No. 212,774 filed 12/27/71, nowUS. Pat. No. 3,772,302, issued Nov. 13, 1973 which in turn is a c.i.p.of Ser. No. 104,784, filed 1/7/71, now abandoned, which is a c.i.p. ofSer. No. 837,354, filed 6/27/69, now abandoned, which is a c.i.p. ofSer. No. 741,914, filed 7/2/68, now abandoned.

BRIEF SUMMARY OF THE INVENTION The invention relatesto a process forpreparing quinine, quinidine, isomers and derivatives thereof whichcomprises:

a. condensing the correspondingly substituted 4- methylquinoline withracemic or optically active cis or trans l-acyl (or 1-H)-3-vinyl(orlower alkyl)- 4-piperidineacetic acid ester to yield the correspondingracemic or optically active cis or trans 4- 3-[1-acyl)or l-H)-3-vinyl)orlower alkyl)-4- piperidyl]-2-oxo-propyl}quinoline;

b. deacylating, if necessary, and reducing the product of step (a) toyield the corresponding racemic or optically active epimeric 4- cis ortrans-3-[3- vinyl(or lower alkyl)-4-piperidyl]-Ze-hydroxypropyl}quinolines. If desired, this reaction product can beacylated to yield racemic or optically active epimeric 4- cis ortrans-3-[3- vinyl(or loweralkyl)-4-piperidyl]-2eacyloxypropyl}quinolines or dehydrated to yieldracemic or optically active cis or trans 4-{cis or trans 3-[3-vinyl(orlower piperidyllprop-l-enyl}quinolines;

c. an alternate process comprises condensing the correspondinglysubstituted 4-methylquinolinc with racemic or optically active cis ortrans 1-acyl-3- vinyl(or lower alkyl)-4-piperidine-acetaldehyde to yieldthe corresponding racemic or optically active epimeric 4-{cis ortrans-3-[ l-acyl-3-vinyl(or loweralkyl)-4-piperidyl]-26-hydroxypropyl}quinolines, and deacylating thisreaction product to yield the corresponding racemic or optically activeepimeric 4- {cis or trans-3-[3-vinyl (or lower alkyl)-4-piperidyll-2e-hydroxypropyl}quinolines;

d. cyclizing the hydroxy, acyloxy or propl -enyl quinoline product ofstep (b) or (c) to yield the corresponding racemic or optically active4- {oz-[5- vinyl(or lower alkyl)-2-quinuclidinyl]- methyl}quinoline,epimeric in positions 2 and 5;

e. hydroxylating the product of step (d) to yield the correspondingracemic or optically active a-[S- vinyl(or loweralkyl)-2-quinuclidinyl1-4 quinolinemethanol, epimeric in positions a, 2and 5; and

f. recovering the desired reaction product.

An alternate process comprises:

g. halogenating the product of step (a) above to yield the correspondingracemic or optically active epimeric 4-{cis or trans 3-[l-acyl-3-vinyl(or loweralkyl)-4-piperidyl]-le-halo-2-oxopropyl}quinolines;

h. reducing the product of step (g) with subsequent cyelization to yielda mixture of the corresponding racemic or optically active epimeric 4-cis or 2 trans-3-[ l-acyl-3-vinyl(or lowerpiperidyl]-le,2e-oxapropyl}quinolines; deacylating the product of step(g) to yield a mixture of the corresponding racemic or optically ac- 5tive epimeric 4-{cis or trans 3-[3-vinyl(or loweralkyl)-4-piperidyl]-le,2e-oxapropyl}quinolines;

j. cyclizing the product of step (h) to yield the corretive cis or trans7-acyl-l-nitroso-decahydro-ZH-.

pyrido[3,4-d]azepin-2-one; b. pyrrolyzing the reaction product of step'(a) to yield the corresponding racemic or optically active cis or transl-acyl-3-vinyl-4-piperidineacetic acid;

and v c. hydrolyzing, if desired, and esterifying the reaction mic oroptically active cis or trans l-acyl(or 1-H)- 3-vinyl-4-piperidineaceticacid ester; and

d. reducing and acylating the reaction product of step (c) to yieldracemic or optically active cis or transl-acyl-3-vinyl-4-piperidineacetaldehyd e.

In a further aspect, the invention relates to an alternate process forpreparing racemic or optically active cis and trans l-acyl(or1-H)-3-vinyI-4-piperidineacctic acid and esters thereof by:

a. alcoholizing a racemic or optically active cis or trans cally activecis or trans l-acyl-3-(2-aminoethyl)-4- piperidineacetic acid esters;

b. methylating the reaction product of step (a) to yield thecorresponding racemic or optically active cis or transl-acyl-3-(Z-dimethylaminoethyl)-4- piperidineacetic acid esters;

c. oxidizing the reaction product of step (b) to yield the correspondingracemic or optically active cis or trans l-acyl-3-(Z-dimethylaminoethyl)4- piperidineacetic acid ester N-oxide; and

d. pyrolyzing the reaction product of step (c) to yield the desiredacetic acid and esters thereof.

In still another aspect, the invention relates to a process forpreparing racemic or optically active cis or trans7-acyldecahydro-2H-pyrido[3,4-d1azepin-2-one which comprises:

a. hydrogenating a racemic or optically active2-acyll,3,4,7,8,8a-hexahydro-6( 2H )-isoquinolone to yield thecorresponding racemic or optically active cis or trans2-acyloctahydro-6(2H)-isoquinolone;

and

65 b. converting the reaction product of step (a),

through a Schmidt Rearrangement, to the corresponding racemic oroptically active cis or trans 7- acyl-decahydro-2H-pyrido[ 3,4-d1azepin-2-one.

product of step (b) to yield the corresponding racc- 7acyl-decahydro-2H-pyrido[3,4-d1azepin- 2-one to yield the correspondingracemic or opti- Alternatively, by a proccsswhich comprises:

a. converting, through 21 Schmidt Rearrangement, a

racemic or optically active 2-acyl-l ,3,4,7,8,8-hexahydro-6(2H)-isoquinolone to the corresponding racemic or opticallyactive 2-acyll,2,3,4,7,8,9,9a-octahydro-6H-pyrido[3,4- dlazepin--one;and Y b. hydrogenating the reaction product of step (a) to yield thecorresponding racemic or optically active cis or trans7-acyldecahydro-2H-pyrido[3,4-

I dlazepin-Z-one.

In yet another aspect, the invention relates to novel compounds.

DETAILED DESCRIPTION OF THE INVENTION The term lower alkyl asused hereindenotes a hydrocarbon group containing 1-7 carbon atoms, such as methyl,ethyl, propyl, butyl and the like; methyl and ethyl are preferred. Theterm lower alkoxy" denotes a lower alkyl ether group in which the loweralkyl moiety is described as above, such as methoxy, ethoxy, propoxy,butoxy and the like; methoxy and ethoxy are preferred. The term halogendenotes all of the halogens, i.e., bromine, chlorine, fluorine andiodine. Preferred are chlorine and bromine. The term acyl denotes loweralkanoyl of 1-7 carbon atoms such as formyl, acetyl, propanoyl,butanoyl, heptanoyl, and the like; ar-lower alkanoyl, preferablyphenyl-lower alkanoyl wherein phenyl may be substituted by one or morelower alkyl, lower alkoxy or halogen groups such as benzoyl and thelike. The term aryl" means phenyl which may be substituted by one ormore lower alkyl, lower alkoxy or halogen groups. The term aralkyl meansa hydrocarbon group of 71 2 carbon atoms such as benzyl, phenethyl,phenylpropyl and the like. The term acyloxy means an acyloxy wherein theacyl moiety is as hereinbefore described, for example, lower alkanoyloxyand ar-lower alkanoyloxy.

The process for preparing quinine, quinidine, isomers and derivativesthereof is exemplified by Reaction Scheme la, la, la, lb, lb and IB.

wherein m is (l, l or 2; R is hydrogen, hydroxy, halogen,trifluoromethyl, lower alkyl, lower alkoxy, or when m is 2, R takentogether with an adjacent R is also methylcnedioxy; R is vinyl or loweralkyl, preferably ethyl; R is hydrogen or lower alkyl; R is hydrogen oracyl; and R is lower alkyl, aryl or ar-lower alkyl. As is evident fromthe above when m is 2, R or the like is individually selected from thevarious groupings hereinbefore described.

Compounds of the formula la and lla above are useful as antimalarial andantiarrhythmic agents.

ln Reaction Scheme la, 4-methyl-quinolines of formula X, which are knowncompounds or are analogs of known compounds readily obtained by knownprocedures, are condensed with l-acyl' (or l-H)-3(R)- vinyl(or loweralkyl)-4l(S)-piperidineacetic acid ester of formula lXa, antipode or itsracemate which are known compounds, are analogs of known compoundsreadily obtained by known procedures, or are prepared as hereinafterdescribed, in the presence of a base, for example, sodium hydride, analkali metal alkoxide such as sodium methoxide, or lithium dialkylaniidesuch as lithium diisopropylamide to yield 4-{3-[ l-acyl(or 1-H)-3-(R)-vinyl(or lower alkyl)-4-(S)-piperidyl]-2- oxopropyl}quinoline offormula Vllla, antipode or its racemate. The condensation is suitablycarried out at room temperature; however, temperatures above or belowroom temperature may be employed, Preferably,

the condensation is conducted at a temperature within:

the range of about 70 and about C. Moreover, the condensation can besuitably carried out in the presence of an inert organic solvent, forexample, a hydrocarbon, such as benzene, hexane and the like, or anether such as ether, tetrahydrofuran or dioxane, or dimethylformamide orhexamethylphosphoramide.

The 4-{3-[l-acyl(or l-H)-3(R)-vinyl(or lower alkyl-)-4-(S)-pipcridyll-2-oxopropyl }quinoline of formula Vllla, antipode orits racemate is converted to the mixture ofepimeric 4-{3-[3(-R)-vinyl(orlower alkyl)-4(S)- piperidyl]-2e-hydroxypropyl quinolines of formulaVla, their antipodes or racemates by simultaneous deacylation, ifnecessary, and reduction, The deacylation and reduction are convenientlyeffected utilizing a reducing agent, for example, diisobutylaluminumhydride. sodium aluminum hydride and the like, in an inert organicsolvent, for example, a hydrocarbon such as benzene or toluene, ether,tetrahydrofuran and the like. The deacylation and reduction are suitablycarried out at room temperature or below, preferably, at a temperaturewithin the range of about 70 to about 25C. The reduction and deacylationcan also be carried out stepwise, i.e., by first reducing a compound offormula Vllla, wherein R is acyl, with sodium borohydride, followed bydeacylation utilizing, for example, aqueous.

hydrochloric or sulfuric acid as the deacylating agent. lf desired, thecompound of formula Vla can be esterified to the corresponding mixtureof epimeric 4-{3- [3(R)-vinyl(or loweralkyl)-4-(S)-piperidyl]-2eacyloxypropyl}quinolines of formula Vllla,their antipodes or racemates utilizing known procedures, for example,reaction with the corresponding organic acid in the presence of acatalyst, such as boron trifluoride. Alternatively, if desired, thecompound of formula Vla can be converted to cis and trans4-{3(R)-vinyl(0r lower alkyl)-4 (R)-piperidyl]-prop-l-enyl}quinolines offormula Va, their antipodes or racemates utilizing a dehydrating agentsuch as thionyl chloride, phosphorus oxychloride, phosphoruspentachloride and the like, in the presence of an organic base, forexample, a tertiary amine such as pyridine, triethylamine and the like,at a temperature within the range of about 0 to about room temperatureThe cyclization of epimeric 4-{3-[3(R)-vinyl(or'loweralkyl)-4-(S)-piperidyl]-2e-hydroxy(or acyloxy temperature withinthe range of about 25 to about C. Moreover, the cyclization can beconveniently I conducted in the presence of an inert organic solvent,for example, a hydrocarbon such as benzene or toluene, or an ether, suchas diethyl ether or tetrahydrofuran.

The hydroxylation of the compounds of formulas Illa and lVa or theirracemates to a(R)-[5(R)-vinyl(or loweralkyl)-4(S)-quinuclidin-2(S)-yl]-4- quinolinemethanol of formula la, itsantipode or racemate and a(S)-[5(R)-vinyl(or lower alkyl)-4(S)-quinuclidin-2(R)-yl]-4-quinolinemethanol of formula lla, its antipode orracemate, respectively, is carried out, for example, in the presence ofmolecular oxygen and a reducing agent, such as dimethylsulfoxide,pyridine, triphenylphosphine, platinum black, or a trialkylphosphite,such as triethylphosphite, or the like, in a strongly basic solution.

A suitable base for the reaction described above comprises, for example,an alkali metal alkoxide, such as potassium t-butoxide, sodiumt-butoxide, sodium isoamylate, sodium methoxide or the like, or analkali metal amide, such as lithium diisopropylamide, sodium amide orthe like. Conveniently, a solvent such as dimethylsulfoxide,dimethylformamide, hexamethylphosphoramide, pyridine, t-butanol, ahydrocarbon such as benzene or toluene, an ether such astetrahydrofuran, dioxane or the like, or mixtures thereof can beutilized. A preferred reaction medium comprises a mixture ofdimethylsulfoxide and t-butanol in the presence of potassium t-butoxide.

Selunnu .ln

V Ia

wherein R,. R and m are as previously described and R',, is acyl.

In Reaction Scheme la an alternative process for the preparation ofcompounds of formula Vla is described. 4-Methylquinolines of formula Xare condensed with l-acyl-3-(R)-vinyl(or lower alkyl)-4(S)-piperidineacetaldchyde of formula XXllla, its antipode or racemate whichare new compounds and are prepared as hereinafter described, in thepresence of base, for example, sodium hydride, an alkali metal alkoxidesuch as sodium methoxide, or lithium dialkylamide such as lithiumdiisopropylamide to yield the mixture of epimeric 4-{3-[l-aeyl-3(R)-vinyl(or lower alkyl)- 4(S)-piperidyll-Ze-hydroxypropyllquinolines of formula XXlVa, their antipodes or racemates. Thecompounds of formula XXlVa are deacylated to the corresponding mixtureof epimeric 4-{3-[3(R)-vinyl(or loweralkyl)-4(S)-piperidyl]-2e-hydroxypropyl}quinolines of formula Vla, theirantipodes or racemates, utilizing a deacylating agent, for example,alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide,a reductive deacylating agent such as lithium aluminum hydride. sodiumaluminum hydride, diisobutyl aluminum hydride and the like. Preferably,the deacylation is suitably carried out at room temperature; however,temperatures above and below room temperature may be employed. Moreover,the deacylation can be suitably carried out in the presence of an inertorganic solvent for example, a lower alkanol, such as methanol orethanol, or an ether, such as tetrahydrofuran or dioxane.

Sulivnw la (Ri)m XXII-a IIa of formula XXa, their antipodes orracemates, respectively, is effected utilizing a halogenating agent suchas N-bromo-suceinimidc, N-chloro-succinimide, N- bromoacetamide and thelike. The halogenation can be conducted in an inert organic solvent, forexample, a hydrocarbon such as benzene, toluene and the like, ahalogenated hydrocarbon such as carbon tetrachloride; an ether such asdiethylether, tetrahydrofuran, dioxane and the like. Conveniently, thereaction can be initiated by a free radical catalyst such asdibenzoylperoxide or by irradiation with infrared. The temperature isnotcritical, however, it is preferred to conduct the reaction at atemperature in the range of about room temperature and the refluxtemperature of the reaction mixture.

The conversion of the epimeric compounds of formula XXa, their antipodesor racematcs to the corresponding mixture ofdiastereomeric 4-{ 3-[l-acyl-3(R)- vinyl(or lower alkyl)-4(S)-piperidyl]-l6,26-oxapropyl}quinolines of the formula XXla, their antipodes or racematescan be effected utilizing a reducing agent, for example, alkali metalhydrides such as sodium borohydride, potassium borohydride, lithiumtritertiarybutoxyaluminum hydride and the like. The reas methanol,ethanol and the like, hydrocarbons such as toluene and the like, etherssuch as diethylether, tetrahydrofuran and the like. The deacylationtemperature is not critical. Conveniently, it may be in the range ofabout -7()C. to about the reflux temperature of the reaction mixture.

The conversion of the compounds of formula XXlla to the correspondingmixture comprising a(R)-[5(R)- duction is conveniently effected in aninert organic solvinyuor lower 4 s i lidi g S 11-4- Vent for p aliphaticalcohols Such as methanol quinolinemethanol of formula Ia, its antipodeor raceethanol and the like; ethers such as diethylether, tetramate anda(s) [(R) vinyl(or lower alkyl) 4(s) hydrofumm dioxanc and the like, ata temperature in quinuclidin-2(R)-yl]-4-quinolinemethanol of formula therange of about 70C. an abOuOt the fefluX {mm 15 Ha, its antipode orracemate is effected by reaction perature of the reactio m with a weakorganic or inorganic protonic acid, for ex- ThC COllVClSlOH Of thecompound of formula XXIZI t0 ample water ammonium hloride, lQweralkanols uch the corresponding miXture 0f th diaslefeOmeric as methanol,ethanol and the like, Lewis acids such as l3(R)- inyl( r lower y )-p p ylaluminum oxide, aluminum chloride, boron trifluoride x pr pynquin 0fthe formula X thcif and the like. Conveniently, conversion is conductedin tipodes or racemates is effected using a deacylating h presence of aninert organic solvent, for example, ag nt, f r example. alkal y r xi has odi m carbon disulfide, hydrocarbons such as benzene, toluhydroxidc.po i m hydr xide. or a r ing d ucyone and the like, chlorinatedhydrocarbons such as dilu ing g n f r x pl i lkylalumin hy ridchloromethane, ,carbontetrachloride, chloroform and such asdiisobutylaluminum hydride, or an alkali metal the like, and ethers suchas diethylether, tetrahydroaluminum hydride such as lithium aluminumhydride, furan, dioxane and the like. The temperature of the resodiumaluminum hydride and the likeJThe deacylaaction is not critical.Conveniently, it may be in the tion is conveniently conducted in thepresence of an range of about 0C. and about the reflux temperature inertorganic solvent, for example, lower alkanols such of the reactionmixture.

" ehe iiie ib i i C CH; COORa R2 H H\ N-R; qgn I t,

( dm w N7 X I'Xb VIIIb m H R R2 H I NH N-H NH J M l) llfL-CHQ IB H l H 001-1 o -R r (Om 1 l)m (B1),

Vb VIb VIIb wherein R R R R R and m are as previously described. I

The hereinafter described reaction steps of Reaction Scheme lb areeffected utilizing the procedures and conditions set forth in Scheme la.The 4-methylquinoline of formula X in condensed with l-acyl(or l-H)-3(S)-vinyl(or lower alkyl)-4(S)-piperidineacetic acid ester offormula lXb, its antipode or racemate to(S)-piperidyl]-2-oxopropyl}quinoline of formula Vlllb, its antipode orracemate. The compound of formula Vlllh is deacylated, if necessary, andreduced to the mixture of epimeric 4-{3-[3(S)-vinyl(or lower alkyl)-4(S)-piperidyll-Ze-hydroxypropyl }quinolines of formula Vlb, theirantipodes or racemates. lf desired,the compounds of formula Vlb can beesterified to the mixture of epimeric 4- 3-[3(S)-vinyl(or loweralkyl)-4(S)- piperidyll-Ze-acyloxypropyl quinolincs of formula Vllh,their antipodes or racemates or, alternatively, it can be converted tocis and trans 4-{3-[3(S)-vinyl(or lower alkyl)-4(R)-piperidyl]-propl-enyl}quinolines of formula Vb, their antipodes orracemates. The compounds of formula Vb, Vlb or Vllb are cyclized to4-{a- [5(S)-vinyl(or lower alkyl)-4(S)-quinuclidin-2(S) and2(R)-yl]-methyl}quinolines of formulas lllb and [Vi], their antipodes orracemates. The compounds of formulas lllh and IV!) are hydroxylated toa(R)-[5(S)- vinyl(or lower alkyl)-4(S)-quinuclidin-2(S)-yl]-4-quinolincmethanol of formula lb, its antipode or racemate anda(S)-[5(S)-vinyl(or lower alkyl)-4(S)-quinuclidin-2(R)-yll-4-quinolinemethanol of formula [[0, its antipode orraeemate, respectively.

Scheme 11) /C1IO R2 1r out 11 R2 on)... H

| on 1V4 X XXIIIb XXIVb VIb wherein R R R' and m are as previouslydescribed.

The hereinafter described reaction steps of Reaction Scheme lb areeffected utilizing the procedures and conditions set forth in Scheme la.4-Methyl-quinolines of formula X are condensed with l-acyl-3(S)-vinyl(orlower alkyl)-4('S)-piperidineacetaldehyde of formulacan also be effectedutilizing molecular oxygen and a catalyst such as platinum,tris(tripenylphosphine )rhodium chloride or the like or by oxidationutilizing a compound such as selenium dioxide, ruthenium tetroxide,palladium acetate, mercuric acetate, thallium triacetate, manganesedioxide, cerium (IV) oxide, or the like.

Alternate procedures for the conversion of the compounds of FormulaVla,b to the corresponding compounds of Formula llla,hlVa,h areexemplified in Reaction Scheme V,

XXXI

XXXIII 1112., b-IVa, b

The conversion of compounds Vla,h to the corre sponding compounds offormula XXXl is effected utilizing a chloroformate such asbenzylchloroformate. The compounds of formula XXXl are converted to thecompounds of formula XXXlI by tosylation with a compound such asp-toluenesulfonylchloride or ptolueneulfonic acid anhydride in a solventsuch as pyridine. The conversion of the compounds of formula XXXll tothe corresponding compound of formula XXXlll is effected by the removalof the N- carbobenzoxy group utilizing, for example, aceticacid/hydrogen bromide mixture. The cyclization of the compounds offormula XXXllI to the corresponding compound of formula llIa,h-lVa,b iseffected by heating in an organic solvent such as methanol, ethanol,dimethylformamide, dimethylsulfoxide and the like.

(EHOPQCH, NJ

XXXII Scheme Ib 1 1n)... (R1)... w N

wherein R,, R R,,, m and X are as previously described.

in Reaction Scheme lh", an alternative process for the conversion ofcompounds of formula Vlllh' to the compounds of formulas lb and III) isdescribed. The conversion of the 4-{3-[ l-acyl-3(S)-vinyl(or loweralkyl)-4(S)-piperidyl]-2-oxopropyl}quinoline of formula Vlllh, itsantipode or raeemate to the corresponding mixture of epimeric 4-{3-[l-acyl-3(S)-vinyl(or loweralkyl)-4(S)-piperidyl]le-halo-Z-oxopropyl}quinolines of formula XXb,their antipodes or racemates, respectively, is effected utilizing ahalogenating agent such as N-bromo-suceinimide, N-chloro-succinimide, N-bromoacetamide and the like. The halogenation can be conducted in aninert organic solvent, for example, a hydrocarbon such as benzene,toluene and the like, a halogenated hydrocarbon such as carbontetrachloride; an ether such as diethylether, tetrahydrofuran, dioxaneand the like. Conveniently, the reaction can be initiated by a freeradical catalyst such as dibenzoylperoxide or by irradiation withinfrared. The temperature is not critical, however, it is preferred toconduct the reaction at a temperature in the range of about roomtemperature and the reflux temperature of the reaction mixture.

The conversion of the epimeric compounds of formula XXh, their antipodesor racemates to the corresponding mixture of diasteromeric4-{3-[l-acyl-3(S)- vinyl(or lower alkyl)-4(S)-piperidyl]-16,25-

oxapropyl}quinolines of the formula XXlh, their antipodes or racematescan be effected utilizing a reducing agent, for example, alkali metalhydrides such as sodium borohydride, potassium borohydride, lithiumtritertiarybutoxyaluminum hydride and the like. The reduction isconveniently effected in an inert organic solvent, for example,aliphatic alcohols such as methanol, ethanol and the like; ethers suchas diethylether, tetrahydroturan, dioxane and the like, at a temperaturein the range of about 70C. and about the reflux temperature of thereaction mixture.

The conversion of the compound of formula XXlb tothe correspondingmixture of the diastereomeric 4-{3- [3(S)-vinyl(or loweralkyl)-4(S)-piperidyl]-l5,26-

oxapropyl}quinolines of the formula XXllb, their antipodes or racematesis effected using a deacylating agent, for example, alkali hydroxidessuch as sodium hydroxide, potassium hydroxide, or a reducing deacylatingagent, for example, dialkylaluminum hydride such as diisobutylaluminumhydride, or an alkali metal aluminum hydride such as lithium aluminumhydride, sodium aluminum hydride and the like. The deacylation isconveniently conducted in the presence of an inert organic solvent, forexample, lower alkanols such as methanol, ethanol and the like,hydrocarbons such as toluene and the like, ethers such as diethylether,tetrahydrofuran and the like. The deacylation temperature is notcritical. Conveniently, it may be in the range of about C. to about thereflux temperature of the reaction mixture.

The conversion of the compounds of formula XXllb to the correspondingmixture comprising a(R)-[5(S)- vinyl(or lower alkyl)-4(S)-quinoclidin-2(S)-yl]-4-quinolinemethanol of formula lb, itsantipode or raeemate and a(S)-[5(S)- vinyl(or loweralkyl)-4(S)-quinuclidin-2(R)-yl]-4- quinolinemethanol of formula llb,its antipode or racemate is effected by reaction with a weak organic orinorganic protonic acid, for example, water, ammonium chloride, loweralkanols such as methanol, ethanol and the like, Lewis acids such asaluminum oxide, aluminum chloride, boron trifluoride and the like.Conveniently, conversion is conducted in the presence of an inertorganic solvent, for example, carbon disulfide, hydrocarbons such asbenzene, toluene and the like, chlorinated hydrocarbons such asdichloromethane, carbontetrachloride, chloroform and the like, andethers such as diethylether, tetrahydrofuran, dioxane and the like. Thetemperature of the reaction is not critical. Conveniently, it may be inthe range of about 0C. and about the reflux temperature of the reactionmixture.

The various other process aspects of the invention are exemplified bythe following reaction schemes Ila, llb, Illa, lllb and IV.

H L H N N A A XIa 0 R5 0 R Xll'a CO OH COORa LIL/k It l L In n R4 XIIIa0 R IXc wherein R;, and R. are as previously described, and R is loweralkyl, aryl or ar-lower alkyl.

ln Reaction Scheme Ila, the conversion of 7acyldecahydro-2H-pyridol 3( R),4( S )-d]azepin-2-onc of formula Xlu, its antipode or racemate to7-acyl-lnitroso-deeahydro-ZH-pyrido[ 3( R ),4( S )-d l-azepin- 2-one offormula Xlla, its antipode or racemate, respectively, is carried oututilizing a nitrosating agent, such as, for example, sodium nitrite ordinitrogen tetroxide. Conveniently, the reaction can be conducted in thepresence of a solvent, for example, an organic acid such as acetic acid,or a chlorinated hydrocarbon such carbon tetrachloride. The nitrosationis conveniently conducted at a temperature within the range of about Cto about room temperature, preferably at 0C.

The compound of formula Xlla is converted tolacyl-3(R)-vinyl-4(S)-piperidineacetic acid of formula Xllla,itsantipode or racemate, respectively, by pyrolysis, Conveniently, thepyrolysis is conducted at a temperature within the range of about roomtemperature to about 200C, preferably at a temperature within the rangeof about lOOC. to about l30C. Conveniently, a high boiling solvent suchas xylene, deealine and the like, can be utilized in the reaction.

The compound of formula Xllla is converted to lacyl(orI-H)-3(R)-vinyl-4('S)-piperidineacetic acid ester of formula lXc, itsantipode or racemate, respectively, utilizing an esterifying agent, forexample, a lower alkanol, such as methanol, ethanol, propanol and thelike, in the presence of, for example, an inorganic acid such ashydrochloric acid, sulfuric acid and the like. When R is hydrogen,however, the esterification is preceded by hydrolysis in the presenceof, for example, an aqueous inorganic acid, such as hydrochloric acid,sulfuric acid and the like.

Compounds of formula Xla, wherein R is alkyl, for instance, ethyl, canbe prepared as described in Scheme lV.

Scheme lib mate 7 Scheme Illa XIVa COORQ COORI! H l H J)2 lK UZ (V0 O Ru0 Re XVa XVIa COORa IX(c) wherein R R and R are as previously described.

In Reaction Scheme Illa, 7-acyl-decahydro-2H-pyrido[3(R),-4(S)-d]azepin-2-0ne of formula Xla, its antipode orracemate is converted to l-acyl-3(R)-(2-aminoethyl)-4(S)-piperidineacetic acid ester of formula XlVa, itsantipode or racemate, respectively, utilizing an alcoholizing agent, forexample, a lower alkano] such as methanol, ethanol, propanol and thelike, in the presence of, for example, anhydrous inorganic acid such ashydrochloric acid, sulfuric acid and the like. Conveniently, thealcoholysis is conducted at a temperature within the range of about roomtemperature to about the boiling point of the alkanol.

The compound of formula XlVa is converted tolacyl-3(R)-(Z-dimethylaminoethyl)-4(S)- piperidincacetic acid ester offormula X Va, its antipode or racemate, respectively, utilizing amethylating agent such as, for example, formic acid/formaldehyde mixtureor formaldehyde/Raney nickel. The N- methylation is convenientlyconducted at a temperature within the range of about room temperature toabout the boiling point of the methylating agent.

The compound of formula XVa is converted toacyl-3(R)-(Z-dimethylaminoethyl)-4(S)- piperidineacetic acid esterN-oxide of formula XVla, its antipode or racemate, respectively,utilizing an oxidizing agent, for example, hydrogen peroxide or aperorganic acid such as, pcracetic acid. The oxidation is convenientlyconducted in the presence of a solvent, for example, lower alkanol, suchas methanol, ethanol, propanol and the like, or a hydrocarbon such asbenzcne and the like. The oxidation is conveniently conducted at atemperature within the range of about to about room temperature,preferably at 0C.

The compound of formula XVla is converted to laeyl(orl-H)-3(R)-vinyl-4(S)-piperidineacetic acid ester of formula lXc, itsantipode or racemate, respectively, by pyrolysis. Such pyrolysis isconveniently conducted at a temperature in the range of about 80 toabout 200C, preferably at a temperature within the range of about 90 toabout 125C. When R is hydrogen, however, the pyrolysis is followed byhydrolysis and reesterification.

wherein R .,,R and R are as previously described.

In a like manner, in Reaction Scheme lllb,7-acyldecahydro-2H-pyrido[3(S),4(S)-d]azepin-2-one of Formula Xlb, itsantipode or racemate is converted tol-acyl-3(S)-(2-aminoethyl)4(S)-piperidineacetic acid ester of FormulaXIV/v, its antipode or racemate, respectively. The compound of FormulaXlVh is converted to l-acyl-3(S)-(Z-dimethylaminoethyl)-4(S)-piperidineacctic acid ester of Formula XVh, its antipode or racemate,respectively. The compound of Formula XVh is converted tol-acyl-3(S)-(2- dimethylaminoethyl)-4(S)-piperidineacetic acid esterN-oxide of Formula XVlh, its antipode or racemate, respectively. Thecompound of Formula XVlh is converted to l-acyl(or l-H)-3(S)-vinyl-4(S)-'piperidineaectic acid ester of Formula lXd, its antipode or racematc.

n Scheme IV 0 H 1| Q l 0 Rs I XVII XVIIIa.

T H K/ 1r 1 H (H l N N O Ra 0 Rs XVIIIb XIb wherein R is as previouslydescribed.

In the Reaction Scheme IV, racemic 2-acyll,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone of formula XVll is converted to the racemic cis andtrans Z-acyloctahydro-6( 2H isoquinolones of formula XVIlla and XVIllb,respectively, utilizing a hydrogenating agent, for example, hydrogen inthe presence of palladium or rhodium catalyst. Conveniently, thehydrogenation can be conducted in the presence of a solvent, forexample, a lower alkanol such as methanol, ethanol, propanol and thelike, with or without an inorganic acid such as hydrohalic acid, forexample, hydrochloric acid and the like. The hydrogenation can beconveniently conducted at a temperature within the range of about roomtemperature and about 50C.

The racemates of the compounds of formula XVIlIa or XVlllh are resolvedto the corresponding optical antipodes by conventional methods which arefurther illustrated by Examples 3, 4, 5.

The conversion of 2-acyl-4a(S),8a(R)-octahydro- 6(2H)-isoquinolone offormula XVllla, its antipode or raccmate to7-acyldccahydro-2H-pyrido[3(R),4(S)- djazepin-2-one of formula Xla, itsantipode or racemate, respectively, is carried out utilizing the knownSchmidt rearrangement, i.e., the reaction of the compound of formulaXVllla with sodium azide in the presence of an inorganic acid such assulfuric acid or polyphosphoric acid, with or without solvent, at atemperature within the range of from about to about 150C.

In a like manner, 2-acyl-4a(S),8a(S)-octahydro- 6( 2H )-isoquinolone ofFormula XVlIlb, its antipode or racemate is converted to7-acyl-decahydro-2H- pyrido[3(S),4(S)-d]azepin-2-one of Formula Xlb, itsantipode or racemate, respectively.

The racemic compound of Formula XVII is converted to the racemic2-acyl-l,2,3,4,7,8,9,9aoctahydro-6H-pryido[3,4-d]azepin 6-one of FormulaXIX utilizing the Schmidt rearrangement as hereinbefore described. Thecompound of Formula XIX is converted to the raeemic compound of FormulaXla utilizing a hydrogenating agent such as hydrogen in the presence ofa catalyst, such as rhodium or palladium, in a solvent, for example, analkanol, such as ethanol, methanol and the like, in the presence of aninorganic acid, such as hydrochloric acid. I

In another aspecct, the invention relates to the compounds of formulaslb, llb, lllb, lVb, Va, Vb, Vla, Vlb, Vlla, Vllb, Villa, Vlllb, lXb,Xla, Xlb, Xlla, Xllb, Xlllb, XlVa, XlVb, XVa, XVb, XVla, XVI!) and XlX.

The compounds of formulas lb and llb are useful as antimalarial andantiarrhythmic agents; all the other compounds listed in the aboveparagraph are useful intermediates.

in still another aspect, the invention relates to compounds of theformulas wherein n is O to 2; R is vinyl or lower alkyltR is hydrogen,hydroxy, lower alkyl, lower alkoxy, trifluoromethyl, halogen, or when nis 2, R taken together with an adjacent R is also methylenedioxy; when Ris hydrogen, R is C C alkoxy, lower alkyl, trifluoromethyl or halogen;

when R is other than hydrogen and n is 1, R is lower alkoxy, loweralkyl, hydroxy, hydrogen, trifluoromethyl, halogen, or taken togetherwith an adjacent R is methylenedioxy; and when R is other than hydrogenand n is 2, R is hydrogen, and their antipodes and racematcs.

Also included in the purview of the invention are compounds of theformulas odes and racematcs. Compounds of formulas lllc, llld, lVc andIVd are useful intermediates.

In still another aspect, the invention relates to compounds of theformulas [R2 /Rz J A A a R1 R7- (R1011 (R1011 N 11m N IVo wherein n is 0to 2; R is vinyl or lower alkyl; R is hydrogen, hydroxy, lower alkyl,lower alkoxy, trifluoromethyl, halogen, or when n is 2, R takentogctherwith an adjacent R is also methylenedioxy; when R is hydrogen, R is C Calkoxy, lower alkyl, trifluoromethyl or halogen; when R is other thanhydrogen and n is 1, R is lower alkoxy, lower alkyl, hydrogen,trifluoromethyl, halogen, or taken together with an adjacent R ismethylenedioxy; and when R is other than hydrogen and n is 2, R ishydrogen and their antipodes and racemates.

As is evident from the above R or R or the like are individuallyselected from the various groupings hereinbefore described. Moreover,when m or n is 2, R or R or the like can additionally form withanadjacent R or R or the like the methylenedioxy radical. Thus, eitherwhen m or n is l or 2, R or R or the like can individually alsorepresent hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy ortrifluoromethyl. Additionally, when m or n is 2, two adjacent groupingsof R or R can together represent methylenedioxy.

In yet another aspect, the invention relates to compounds of theformulas CHaO \NJ IIII wherein R is methyl or C3-C1 lower alkyl, theirantipodes and racemates. Compounds of formulas Ille, lllf, [Ve and lVfare useful intermediates.

In a further aspect, the invention relates to compounds of the formulaswherein n is to 2;

R is vinyl or lower alkyl;

R is hydrogen, hydroxy, lower alkyl, lower alkoxy, trifluoromethyl orhalogen, and when n is 2, R taken together with an adjacent R is alsomethylenedioxy; when R is hydrogen, R is C -C alkoxy, lower alkyl,trifluoromethyl or halogen;

when R is other than hydrogen and n is l, R, is lower alkoxy, loweralkyl, hydrogen, trifluoromethyl or halogen, or taken together with anadjacent R is methylenedioxy; and when R,, is other than hydrogen and nis 2, R is hydrogen, and their antipodcs and racemates, andpharmaceutically acceptable acid addition salts.

Exemplary of the compounds of formulas lo and He are:

6,8-dimethoxy-a( R H S )-ethyl-4( S)-quinuclidin-2(S)-yl1-4-quinolineniethanol [hereinafter referred to as 6', 8'-dimethoxy-3-epidihydrocinchonidinelits antipode and racemic analog;7-chloro-a(R)-[5(S)-cthyl-4(S)-quinuclidin-2(S)- yl1-4-quinolinemethanol[hereinafter referred to as 7'-chloro-3-epi-dihydrocinchonidine] itsantipode and racemic analoy', 6,7-methylenedioxy-a(R)-[5(S)-ethyl-4(S)-quinuclidin-2(S)-yl]-4-quinolinemethanol [hereinafter referred to as 6,7'-methylenedioxy-3-epidihydrocinchonidine] its antipode and racemicanalog',

7-trifluoromethyl-a(R)-[5(S)-ethyl-4(S)-quinuclidin-2(S)-yl1-4-quinolinemethanol [hereinafter referred to as7-trifluoromethyl-3-epidihydrocinchonidine] its antipode and racemicanalog;

6,8-dimethoxy-a(S)-[5(S)-ethyl-4(S)-quinuclidin-2(R)-yl]-4-quinolinemethanol [hereinafter referred to as 6,8'-dimethoxy-3-epidihydrocinchonine] its antipode and racemie analog;

7-chloro-a(S)-[5(S)-ethyl-4(S)-quinuclidin-2(R)- yll-4-quinolinemethanol[hereinafter referred to as 7-chloro-3-epi-dihydrocinchonine] itsantipode and racemic analog;

6,7-methylenedioxy-a(S)-[5(S)-ethyl-4(S)-quinuclidin-2(R)-yl]-4-quinolinemethanol [hereinafter referred to as 6,7-methylenedioxy-3-epidihydrocinchonine] its antipode and racemicanalog;

7-trifluoromethyl-a(S)-[5(S)-ethyl-4(S)-quinuclidin-2(R)-yl1-4-quinolinemethanol [hereinafter referred to as7-trifluoromethyl-3-epidihydrocinchonine] its antipode and racemicanalog. I

Also included in the purview of the invention are compounds of theformulas R2 Rz' A A I. ll 1,1, HoI HSFP cmoonto \N/ \NJ Id and IIdwherein R is vinyl, methyl or C -C alkyl, their antipodes and racematesand pharmaceutically acceptable acid addition salts.

Also included in the purview of the invention are compounds of theformula:

The antipode of 6-methoxy-a(R)-[5(S)-ethyl-4(S)-quinuclidin-2(S)-yl]-4-quinolinemethanol [hereinafter referred to as 6metho y epi dihydrocinchonidine or 3-epi-dihydroquinine] and its raeemicanalog (Compound'A) and The antipode of 6-methoxy-a(S)-[5(S)-ethyl-4(S)-quinuclidin-2(R)-yl]-4-quinolinemetlgnti[hereir after referred to as6'-meth0Xy-3-epidihydrocinchonine or 3-epi-dihydroquinidine} and itsrace mic analog (Compound B). The compounds of formulas lc, ld, llc andIld, as well as Compounds A and B, are useful also as antimalarialantiarrhythmic agents.

The compounds of the formula lXa have demonstrated cardiovascularactivity, such as, hypotensive activity. The-pharmacologically usefulcardiovascular activity is demonstrated in warm-blooded animalsutilizing standard procedures. For example, the test compound isadministered to anesthetized (30 mg/kg sodium pentobarbital),artificially respired (Palmer Pump) dogs. Femoral arterial bloodpressure and respiratory resistance (measured in terms of pressure) arerecorded on a direct writing oscillographic recorder. A series ofcontrol" responses of the blood pressure and respiration are obtainedand duplicated. The control procedures used are; intravenouslyadministered. norepinephrine l 'y/kg), histamine l y/kg), serotonin (25'y/kg) and hyperstensin (0.5 y/kg), as well as the bilaterial occlusionof the carotid arteries and the electrical stimulation of the centralportion of a severed vagus nerve (SV, 50 c.p.s., 10 sec.). Each of thecontrol procedures is administered at 5-minute intervals. Five minutesafter the series of control responses, the drug to be tested isintravenously administered and its effects recorded. The series ofcontrol procedures is repeated after dosing to determine the effect ofthe compound on these standard responses. If the control responses areunaltered by the test drug, a second compound is administered and theprocedure repeated. If the test compound alters the blood pressure orthe control responses, the control procedures are repeated at convenientintervals until the animal has returned to its predose status or a newphysiological status is established.

When meroquinene-t-butylester d-monotartrate of the formula "W! COO C(CHd-monotartrate is utilized as the test substance at a dose of 4 mg/kg.intravenously, the following results are obtained:

blood pressure 25 for 35 minutes serotonin N.E.

Central Vagus Stimulation slight inhibition Carotid Occlusion blockingHypertension N.F.. Norepinephrine slight inhibition Histamine slightinhibition The compounds of Formula lXa also exhibit anticstrogenicactivity. This useful estrogenic activity is demonstrated inwarm-blooded animals. For example, the test Compound is administeredonce daily for three consecutive days to groups of ten immature femalerats (4()50 grams). On the first treatment day, all rats are injectedsubcutaneously with 0.25 meg. estradiol in sesame oil. On the fourthday, uteri are removed at autopsy and weighed on a torsion balance.

When meroguqinene-t-butylester d-monotartrate is utilized as the testsubstance at a dosage of 1 mg/kg. p.o., an 1 1 percent antiestrogeninhibition is observed with a -l2percent uterine change.

The compounds of formulas la, lla, lb and llb, including compounds ofthe formulas lc, la, He and lld, as well as compounds A and B, and theirpharmaceutically acceptable acid addition salts possess antimalarial andantiarrhythmic properties and are therefore useful as anti-, malarialand antiarrhythmic agents. Their pharmacologically useful antiarrhythmicactivity is demonstrated 7 in warm-blooded animals utilizing standardprocedures, for example, the test compound is administered to preparedmongrel dogs. The chest cavity of the ex pcrimental animal previouslyanesthetized using a combination of sodium barbitol, 300 mg/kg. andpentobarbitol, mg/kg, i.c., is opened up through the third rightinterspacc under artificial respiration and the pericardium is cut andsutured to the wall of the thorax so as to maintain the heart in apericardial cradle throughout the course of the test procedure. Arterialpressure is monitored by inserting a polyethylene cannula into the aortavia the left carotid artery and is measured with an appropriate Stathampressure transducer. During the course of the experiment, electricalactivity of the heart is viewed both on an oscilloscope and recorded ona Sanborn polyviso using standard ECG lead ll. The heart is alsoobserved visually. The antiarrhythmic assay of the test drug isundertaken using a modification of the method of Scherf and Chick, 1951.A dripping of l percent solution of acetylcholine is applied to thesinus node and the atrium is irritated by pinching with a pair offorceps. This procedure a continuous artiral arrhythmia which mostlyconsists of atrial fibrillation. Since hypokalemia produces asusceptibility to atrial fibrillation (Leveque, 1964), 2 units/kg. ofinsulin is administered 30 minutes before the start of the acetyleholinedrop. Once atrial fibrillation is established, there is a 10-minutewaiting period before the test drag is administered. The test drugs areadministered at the rate of l mg/kg/minute until normal sinus rhythmappears or until 30 mg/kg. of drug is administered.

When 6methoxy-a(R)-[5(R)-ethyl-4(S)- quinuclidin-2(S)-yl-4-quinolinemethanol is utilized as the test substance at a dosage of about 4.0mg/kg., an

antitibrillatory effect is observed for more than 60 minutes.

Thcir pharmacological useful antimalarial activity is demonstrated inwarm-blooded animals using standard sulfuric acid, and the like.

procedures, for example, the test substance is administered to albinemice in variable amounts. Albine mice are inoculated with about 5-10million red cells infected with P. Bergel. Treatment is started on thefirst day after inoculation, and the drug is administered per os during4 consecutive days. On the seventh day of infection, smears are madestained with giemsa and microscopically examined for P. Bergei.

When racemic 7-methoxy-dihydrocinchonidine dihydrochloride or racemic7-methoxydihydrocinchoninc dihydrochloride is utilized as the testsubstance at dosages in the range of mg/kg. to about 250 mg/kg., themicroscopical examination of the blood smears in free of P. Berghei(negative). When 6-methoxy-oz(R)-[5(R);ethyl-4(S) quinuclidin-2(S)yl]-4-quinolinemethanol [dihydroquinine] or6-methoxy-a(R)-[5(R)-ethyl-4(S)- quinuclidin-2(S)-yl-4-quinolinemethanolis utilized as the test substance at a dose of about 200 mg/kg., themicroscopical examination of the blood smears is free of P. Berghei(negative). The compounds of formulas la, lla, lb and llb, including thecompounds of formulas Ic. Id. [10 and 11d. as well as compounds A and B,and their pharmaceutically acceptable acid addition salts have effectsqualitatively similar. for example, to those of quinine and quinidine,known for their therapeutic uses and properties. Thus. the compounds ofthe invention demonstrate a pattern of activity associated withantimalarials and antiarrhythmics of known efficacy and safety.

F u rthe rTnore the compo unds of the formulas la, Il a, lb and llb,including the compounds of formulas lc, ld, He and lld, as well ascompounds A and B, can utilized as flavoring agents in beverages in thesame manner as quinine is now used for this purpose.

The compounds of formulas la, lla, lb and llb, incluidng the compoundsof formulas lc, ld, llc and lld, as well as compounds A and B, form acidaddition salts and such salts are also within the scope of thisinvention. Thus, the compounds of formulas la, lla, lb and 1112,including the compounds of formulas lc, ld, He and lld, as well ascompounds A and B, form pharmaceutically acceptable addition salts with,for example, both pharmaceutically acceptable addition salts with, forexample, both pharmaceutically acceptable organic and inorganic acids,such as acetic acid, succinic acid, formic acid, methanesulfonic acid,p-toluene-sulfonic acid, hydrochloric acid, nitric acid, phosphoricacid,

The products of the invention can be incorporated into standardpharmaceutical dosage forms, for example, they are useful for oral orparenteral application with the usual pharmaceutical adjuvant materials,e.g., organic or inorganic inert carrier materials such as water,gelatin, lactose, starch, magnesium stearate, talc, vegetable oils,gums, polyalkyleneglycols, and the like. The pharmaceutical preparationscan be employed in a solid form, e.g., as tablets, troches,suppositories capsules, or in liquid form, e.g., as solutions,suspensions or emulsions. The pharmaceutical adjuvant material caninclude preservatives, stabilizers, wetting or emulsifying agents, saltsto change the osmotic pressure or to act as buffers. They can alsocontain other therapeutically active materials.

The quantity of active medicament which is present in any of theabove-described dosage forms is variable. The frequency with which anysuch dosage form will be administered will vary, depending upon thequantity of active medicament present therein, and the needs andrequirements of the pharmacological situation.

Due to the possible different spatial arrangements of their atoms, it isto be understood that the compounds of this invention may be obtained inmore than one possible stcrcoisomcric form. The novel compounds, asdescribed and claimed, are intended to embrace all such isomeric forms.Accordingly, the examples included herein are to be understood asillustrative of particular mixtures of isomers or single isomers and notas limitations upon the scope of the invention. All temperatures are indegrees eentigrade, unless otherwise mentioned. 7

EXAM PLE 1 Preparation of epimeric 6-methoxy-4-{3-[3(R)-vinyl-4(S)-piperidyl]-2-hydroxypropyl }quinolines from raccmic cis6-methoxy-4-(3-l l-bcnzoyl-3-vinyl-4- piperidyll-2-oxopropyl)quinolineTo a stirred solution containing 2.8 g. of racemic cis 6-methoxy-4--{-3-[ l-benzoyl3-vinyl-4-piperidyl]-2-oxopropyl}- quinoline in 150 ml.of dry toluene at was added dropwise a solution containing 25%diisobutyl aluminum hydride in toluene, while the course of the reactionwas checked by tlc. After l2 ml. were added, the reaction was quenchedby the addition of ml. of an ice cold mixture of water-methanol l :l Theresulting mixture was stirred at The alumina which precipitated was thenremoved by filtration, washed thoroughly with methanol, and the combinedfiltrates were evaporated to dryness. The residue was dissolved indichloromethane, washed with 1N sodium hydroxide and water, dried overanhydrous sodium sulfate and evaporated. The product, racemic epimericcis 6-methoxy-4- {3-[ 3-vinyl-4-piperidyl]-2-hydroxypropyl}quinolineswas dissolved in 40 ml. of acetone, and added to the solution containing1 g. of dibenzoyl-(d)-tartaric acid in 10 ml. of methanol.Crystallization yielded the corresponding dibenzoyl-(d)-tartrate. Themother liquor was converted to the free base which was purified byEXAMPLE 2 Racemic, epimeric trans 6,8-dimethoxy-4-[3-(3-ethylt4-piperidyl)-2-hydroxypropyl}quinolines from racemic trans6,8-dimethoxy-4-[3-(3-ethyl-4-piperidyl)-2- oxopropyl}quinoline To astirred, ice cold solution of 5 g. (0.014 mole) of raccmic trans6,8-dimethoxy-4[ 3-( 3-ethyl-4- piperidyl)-2-oxopropyl]-quinoline in 150ml. of methanol was added 0.9 g. of solid sodium borohydride. Afterstirring for 60 min., 50 ml. of water was added and the methanol wasremoved by evaporation. The aqueous residue was saturated with sodiumchloride and extraeted thoroughly with chloroform-ethanol (9:1 Theextracts were dried (sodium sulfate) and evaporated to give 5 g.(quantitative recovery) of racemic, epimeric trans6,8-dimethoxy-4-[3-(3-ethyl-4-piperidyl)-2- hydroxypropyl)quinolines asa crude oil.

EXAMPLE 3 Preparation of epimeric 6-methoxy-4-{3-[3(R)-vinyl-4(S)-piperidyl]2-hydroxypropyl quinolines from 6-methoxy-4-{3-l3(R)-vinyl-4(S)-piperidyl]-2- oxopropyl}quinoline Asolution containing l.8 g. of 6-methoxy-4-{3-[3(R)-vinyl-4(S)-piperidyl]-2-oxopropyl }quinoline in 20 ml. of methanolwas added to an ice cold solution containing 1 g. of sodium borohydridein 100 ml. of methanol. The solution was stirred at 0 to 2 0 f0r 9 0minutes. After addition of 50 ml. of water, the methanol was removed bydistillation. The remaining aqueous phase was extracted withdichloromethane. The extract was washed with lN aqueouos sodiumhydroxide and water, dried over anhydrous sodium sulfate and evaporatedto dryness. The residue was dissolvedin a small volume of methanol, andadded to a solution con taining 0.98 g. of dibenzoyl-(d)-tartaric acidin acetone. Crystallization yielded the neutral dibenzoyl-(d)- 1tartrates of the epimeric 6-methoxy-4-{3-[3(R)-vinyl-4(S)-piperidyl]-2-hydroxypropyl }quinolines having a melting point-ofl89l90 after recrystallization from methanol-acetone; [0th, =-27.0 (c1.09, methanol).

The free base, epimeric 6-methoxy-4-{3-[3-(R)-vinyl-4(S)-piperidyl]-2-hydroxypropyl }quinolines, was obtained as aviscous, colorless oil; [61],, 396 (c 1.425, chloroform).

EXAMPLE 4 Preparation of epimeric 7-chloro-4-{3-[3(R)-vinyl-4(S)-piperidyl]-2-hydroxypropyl quinolines from 7- chlor'o-4-i.3-[3(R)-vinyl-4(S)-piperidyl]-2- oxopropyl }quinoline To a stirred,ice cold solution containing 1.98 g. of7-chloro-4-{3-[3(R)-vinyl-4(S)-piperidyl]-2- oxopropyl}quinoline in 60ml. of methanol was added 1 g. of sodium borohydride in portions. Afterstirring for l0 minutes, 20 ml. of water were added and the methanol wasevaporated. The remaining mixture was made alkaline with 1N sodiumhydroxide and extracted thoroughly with dichloromethane. The extract waswashed with water, dried over anhydrous sodium sulfate and evaporated toyield 1.61 g. of epimeric 7-chloro-4-{3-[3(R)-vinyl-4(S)-piperidyl]-2-hydroxypropyllquinolines. Theneutral dibenzoyl(d)-tartrate had a melting point of l98l 99 afterrecrystallization from dichloromethane-methanol.

Preparation of Epimerie 6-methoxy-4-{3-[l-benzoyl-3(R)-vinyl-4(S)-piperidyl]-2-hydroxypropyl}quinolines fromo-methoxylepidine and l-benzoyl-3(R)- vinyl-4(S)-piperidineacetaldehydeTo ca. 0.0055 mole of lithium diisopropyl amide [prepared in anatmosphere of dry nitrogen by addition of 0.8 ml. (ca. 0.06 mole) ofdiisopropyl amine to 2.6 ml. of 2.14 M phenyl lithium in hexane] wasadded with stirring a solution of .95 g. (0.0055 mole) of 6-methoxylepidine in 7 ml. of benzene and 25 ml. of tetrahydrofuran. Afterstirring at room temperature for 20 minutes a solution of 0.95 g.(0.0037 mole) of lhenzoyl-3(R)-vinyl-4(S)-pipcridineaeetaldehyde in 14ml. of tetrahydrofuran was added dropwise (30 min.), and the resultingmixture was stirred at room temperature for 15 hours. Water (50 ml.) wasadded, the aqueous phase was extracted thoroughly with ether. Theethereal phase was washed (2 X aq. sodium chloride), dried (sodiumsulfateyand evaporated to dryness. The crude product (2.4 g.) wasabsorbed on 100 g. of neutral alumina, activity 11, and elution withethyl acetate containing 1% of methanol afforded 0.88 g. (55%) ofepimeric 6-methoxy-4-{3-[l-benzoyl-3 (R)-vinyl-4(S)-piperidyll-2-hydroxypropyl }quinolines as a colorless oil.

EXAMPLE 6 Preparation of Epimcric 6-methoxy-4-{3-l3(R)-vinyl-4(S)-piperidyll-2-hydroxypropyl}-quinolines from epimeric6-mcthoxy-4-{3-il1-benzoyl-3(R)-vinyl-4(S)- pipcridyll-2-hydroxypropyl}-quinolincs To a solution of 0.145 g. (0.00033 mole)of epimeric 6-methoxy-4-{3-l l-benzoyl-3( R)vinyl.4(S)-piperidyll-2-hydroxypropyl}-quinolines in 20 ml. of tetrahydrofuran wasadded 0.008g. (0.0015 mole) of sodium aluminum hydride, and the mixturewas stirred at room temperature for 80 min. Ca. 20 ml. of 1N sodiumhydroxide was added, the aqueous phase was extracted thoroughly withether, the ethereal extracts were washed with water, dried (sodiumsulfate) and evaporated to give 0.1 l g. (over 90% recovery) of crudeepimeric piperidyl]-2-hydroxypropyl}quinolines.

EXAMPLE 7 Preparation of epimcric 6-methoxy-4-{3-[3(R)-vinyl-4(S)-piperidyl]-2-acetoxypropyl}quinolines from epimcric6-methoxy-4-{3-[3(R)-viny1-4(S)-piperidyl]-2- hydroxypropyl}quinolinesTo a solution containing 1.15 g. of epimeric 6- methoxy-4- {3-1 3(R)-vinyl-4(S )-piperidyl]-2-hydroxypropyl}quinolines in 40 m1. of glacialacetic acid were added 4 ml. of freshly distilled borontrifluorideetherate. The solution was kept at 50 for 18 hours. Thereafter, thereaction mixture was concentrated in vacuo to about 10 ml.,.and, afteraddition ofice, neutralized (pH ea. 8) with 6N sodium hydroxide. The icecold, alkaline phase was extracted thoroughly with dichloromethane, andthe extracts were washed with water, dried over anhydrous sodium sulfateand evaporated to yield epi meric6-methoxy-4-{3-l3(R)-vinyl-4(S)-piperidyl]-2- acetoxypropyl }quinolinesas colorless glass; al +21.4 (c 0.835, chloroform).

EXAMPLE 8 Racemic, epimeric trans 6,8-dimethoxy-4-[3-(3-ethyl-4-piperidyl)-2-acetoxypropyl] quinolines from racemic, epimeric trans6,8-dimethoxy-4-[3-(3-ethyl-4- piperidyl)-2-hydroxypropylJ-quinolines Toa solution of a crude mixture of 5 g. (ca. 0.014 mole) of racemic,epimcrie trans 6,8-dimethoxy-4-[3-(3-ethyl-4-piperidyl)-2-hydroxypropyl}quinolines in 200 m1. of glacialacetic acid was added 20 ml. of highly distilled borontrifluorideetherate, and the solution was kept at 50 for hours. The acetic acid wasstripped off, ice-water was added, the aqueous solution was neutralizedwith cone. ammonium hydroxide to pH ca. 8 and extracted thoroughly withdichloromethane. The organic extracts were washed (saturated sodiumchloride), dried (sodium sulfate) and evaporated to dryness to give 4.5g. (ca. 80 percent) of racemic, epimeric trans6,8-dimethoxy-4-[3-(3-ethyl-4-piperidyl)2- acetoxypropyllquinolines as acrude oil.

EXAMPLE 9 Preparation of cpimeric 7-chloro-4-{3-l3(R)-vinyl-4(S)-piperidyll-2-acetoxypropyl }quinolines from epimeric7-chloro-4-{3-[3(R)-vinyl-4(S)-piperidyl]-2- hydroxypropyl}quinolines Toa solution containing 0.656 g. of epimeric 7-chloro-4-{3-[3(R)-vinyl-4(S)-piperidyl]-2-hydroxypropyl}quinolines in 30ml. of glacial acetic acid were added 3 ml. or freshly distilled borontrifluo ride etherate. The solution was kept at 50 for 19 hours.Thereafter, the reaction mixture was concentrated in vacuo to about 10ml. Ice was added and the ice cold mixture was neutralized (pH ca. 8)with 6N sodium hydroxide and thoroughly extracted with dichloromethane.The organic layer was washed with water, dried over anhydrous sodiumsulfate and evaporated to dryness. The residue was purified bypreparative thin layer chromatography [chloroform-triethylamine (9:1 )1to yield epimeric 7-chloro-4-{3-l3(R)-vinyl-4(S)-piperidyl]-2-acetoxypropyl}quinolines as a viscous oil.

EXAMPLE 10 Preparation of cis and trans 6-methoxy-4-{3-[3(R)-viny1-4(R)-piperidyl]prop-l-enyl}quinolines from epi- Preparation ofdesoxyquinine [6-methoxy-4- {oz-[5(R)-vinyl-4(S)-quinuclidin-2(S)-yl]-methyl}quinoline] and desoxyquinidine[6-methoxy-4-{a-[5(R)-vinyl-4(S)- quinuclidin-2(R)-y1]-methyl-quinoline] from epimeric6-methoxy-4-{3-13(R)-vinyl-4('S)-piperi-dyl]-2-acetoxypropyl}quinolines.

a. With benzene 1) 5% acetic acid (1) sodium acetate To a solutioncontaining 1.241 g. of the epimeric 6-methoXy-4-{3-[3(R)-vinyl-4(S)-piperidyl]2- acetoxypropyl}quinolines in150 ml. of benzene and 7.5 ml. of glacial acetic acid were added 17 g.of sodium acetate trihydate. The mixture was heated under gentle refluxwith stirrng for 14 hours. After cooling, ml. of ice water were addedand the resulting mixture was made alkaline by addition of 6N sodiumhydroxide. The aqueous phase was extracted thoroughly with either andthe ethereal extracts were washed with water, dried over anhydrousmagnesium sulfate and evaporated. The residue was adsorbed on 30 g. ofneutral alumina column (activity 11); the fractions eluted with ethylacetate were further purified by preparative thin layer chromatographyto yield a mixture of desoxyquinine and desoxyquinidine as a colorlessviscous oil having a specific rotation of [at],, 76.3 (c 1.21, CHCl b.With benzene 10 percent acetic acid thin layer chromatography(chloroform triethylamine, 9:1

EXAMPLE 12 Raccmic 6,8-dimethoxy-3-cpi-dcsoxydihydrocinchonidine andraeemic 6,8-dimethoxy-3-epi-desoxydihydrocinchonine from racemic,epimeric trans 6,8- dimethoxy-4-l 3-( 3-ethyl-4-piperidyl)-2acetoxypropyl]-quinolines To a solution of 4.2 g. of crude raccmic,epimeric trans 6,8-dimcthoxy-4-[3-(3-ethyl-4-piperidyl)-2-acetoxypropyl]quinolincs-in 300 ml. of benzene was added 30 ml. ofglacial acetic acid and 50 g. of sodium acetate trihydrate, and themixture was heated with stirring under gentle reflux for 12 hours. Aftercooling, 200 ml. of ice-water was added, the aqueous phase wasneutralized with cone. ammonium hydroxide to pH ea. 8, separated fromthe benzene layer, and extracted thoroughly with dichloromethane. Thecombined organic layers were dried (sodium sulfate) and evaporated invacuo to give 3.6 g. of crude reaction product. Absorption on 100 g. ofneutral alumina, activity 11, and elution with ethyl acetate afforded2.15 g. (ca. 60 percent) of a mixture of racemic6,8-dimethoxy-3-epidesoxydihydrocinchonidine and racemic 6,8-dimethoxy-3-epi-desoxydihydrocinchonine as a colorless oil.

EXAMPLE 13 Preparation of 7 chlorodesoxycinchonine [7-chloro-4{a-l5(R)-vinyl-4(S)-quinuclidin-2(R)- y1]methyl quinoline] and 7-chlorodesoxycinchonidine [7-chloro-'4- {a-[5(R)-.vinyl-4(S)-quinuclidin-2(S)-yl]-methyl}quinoline] from epimcric 7-chloro-4.-{3-[3(R)-vinyl-4(S)-piperidyl]-2- acetoxypropyl}quinolines To a solutioncontaining 0.363 g. of epimerie 7- chloro-4-{3-[ 3( R )-vinyl-4(S)-piperidyl ]-2-acetoxypropyl}quinolines in 50 ml. of benzene wereadded 2.5 ml. of glacial acetic acid and 5.5 g. of sodium acetatetrihydratc. The mixture was heated under gentle reflux with stirring for1 1 hours. After cooling, 100 ml. of ice water were added, the mixturewas made alkaline with 6N potassium hydroxide and extracted thoroughlywith ether. The ethereal extract was washed with water, dried overanhydrous sodium sulfate and evaporated to dryness. The residue waspurified by preparative thin layer chromatography[chloroform-triethylamine (9:1)] to yield a mixture of7-chlorodesoxycinchonine and 7-chlorodesoxycinchonidine.

EXAMPLE 14 Preparation of desoxyquinine [6-meth0xy-4- {a-[5(R)-viny|-4(S)-quinuclidin-2(S)-yl] methyl}quinoline] and desoxyquinidine[6-methoxy-4-{oz-[5(R)-vinyl-4(S)- quinuclidin-2(R)-yl]methyl}-quinoline] from epimeric6-methoxy-4-{3-l3(R)-vinyl-4(S)-piperidyl]-2-hydroxypropyl}quinolines a.In benzene-acetic acid (4:1) A solution containing 0.350 g. of epimeric6- methoxy-4-{3-[3(R)-vinyl-4(S)-piperidyl]-2- hydroxypropyl}quino1inesin 50 ml. of benzeneacetic acid (4:1 was heated under gentle reflux for29 hours. After the addition of water (about 50 ml.), the aqueous phasewas made alkaline with 6N NaOH and extracted thoroughly with ether. Theethereal extract was washed with water, dried over anhydrous magnesiumsulfate and eva porated to dryness. The residue was separated bypreparative thin layer chromatography (chloroformtriethylamine, 9:1) toyield a mixture ofdesoxyquinine and desoxyquinidine.

b. In benzene-acetic acid (9:1)

A solution containing 176 mg. of the epimeric 6-mcthoxy-4-{3-l3(R(-vinyl-4(S)-piperidyl]-2' hydroxypropyl }quinolines in50 ml. of benzeneacetic acid (9:1 was heated under gentle reflux for 67hours. Thereafter, the reaction mixture was worked-up as in a) to yielda mixture of desoxyquinine and desoxyquinidine.

ExAMPLE 15 Preparation of desoxyquinine and desoxyquinidine from cis andtrans 6-methoxy-4-{3-[3(R)-vinyl-4(R)-piperidyl]-prop-l-enyl}-quinolines I A solution containing 0.11 g. of acrude mixture of cis and trans 6-methoxy-4-{3-[3(R)-vinyl-4(R)-piperidyll-prop-1-enyl}quinolines in 10 ml. of benzene and 1 ml. ofacetic acid was heated under gentle reflux for 4 and /2 hours. Water,about 10 ml., was added. The aqueous phase was made alkaline with 6Naqueous sodium hydroxide and extracted thoroughly with ether. Theethereal extracts were washed with water, dried over anhydrous magnesiumsulfate and evaporated to dryness. The residue was separated byperparative thin layer chromataography [chloroform-triethylamine (9:1)]to yield a pure mixture of desoxyquinine and dcsoxyquindine.

EXAMPLE 16 I Preparation of quinine [6-methoxy a(R)-[5(R)-vinyl-4(S)-quinuclidin-2(S)-yl]-4-quinolinemcthanol] and quinidine[6-methoxy-a(S)-(R)-vinyl-4(S)-quinuclidin-2(R)-ylJ-4-quinolinemethanol| from desoxyquinine and desoxyquinidine.

A solution containing 0.826 g. of a mixture of desoxyquinine anddesoxyquinidine in 40 ml. of dimethylsulfoxide-t-butanol (4:1 wasstirred under an atmosphere of dry oxygen at 20 for about 10 minutes (no0 uptake was observed). To this solution was added 0.6 g. of drypotassium-t-butoxide, and the resulting redbrown solution was stirred at20 while the uptake of oxygen was measured. An almost constant uptake ofabout 2.5 ml./minute was observed until the total uptake reached 68 ml.whereupon, the rate of 0 con sumption slowed down. When 71.5 ml. ofoxygen were consumed, the reaction was quenched by addition of water andfew drops of acetic acid. The resulting light yellow solution wasevaporated to dryness in vacuo (0.1 mm). The residue was dissolved indichloromethane and extracted thoroughly with 2N sulfuric acid. Theacidic extracts were made alkaline and extracted with dichloromethane.The organic phase was washed with water, dried over anhydrous sodiumsulfate and evaporated. The bases thus obtained were crystallized fromethanol to yield quinidine. The mother liquor was separted bypreparative thin layer chromatography(ehloroform-triethylaminc-methanol, 85:l0:5) to yield quinine andquinidine.

Quinidinc was crystallized from ethanol and had a melting point andmixed melting point of l70171 (after drying at 90); [01],, 259.0 (c1.095, ethanol). Ouinine was crystallized as its neutral (d)-tartratemonohydrate and had a melting point and mixed melting point of 207209(dec., crystals start to soften above about 180); [01],, l54.l (c 0.855,methanol).

EXAMPLE l7 Racemic 6.8-dimethoxy-3-epi-dihydrocinchonidine and racemic6,8-dimethoxy-3-epi-dihydrocinchonine from racemic6,8-dimethoxy-3-epi-desoxydihydrocinchonidine and racemie6,8-dimethoxy-3-epi-desoxydihydrocinchonine The reaction was carried outin a 250 ml. three-neck flask connected with a gas burette and fittedwith a gas outlet, an Erlenmeyer flask attached by means of a piece ofgooch rubber, and a magnetic stirrer. A solution of 1.97 g. (0.0058mole) of a mixture of racemic6,8-dimethoxy-3-epi-desoxydihydrocinchonidine and racemic6,8-dimethoxy-3-epi-desoxydihydrocinehonidine in 80 ml. ofdimethylsulfoxide-t-butanol (4:1 was first stirred in an atmosphere ofdry oxygen at 20 for several minutes (no oxygen uptake observed). Then0.975 g. (0.0087 mole) of solid potassium t-butoxide was added in onebatch. The uptake of oxygen was measured while the solution was stirred.After consumption of 145 ml. (ca. 1 molar equivalent, 22 min.), 5 ml. ofwater was added, the pH was adjusted to ca. 8 by addition of acetic acidand the solution was evaporated in vacuo. The crystalline residue wasdissolved in 100 ml. of dichloromethane, washed with 10 percent sodiumbicarbonate (2 X ml.) and with water (1 X 20 ml.). dried (sodiumsulfate). and evaporated to dryness. The crude product was separated bypreparative layer chromatography into 0.826 g. percent) of racemic6,8-dimethoxy-3-epi-dihydrocinchonidine (m.p. 170-175, from acetone) and.697 g. (33 percent) of racemic 6,8-dimcthoxy-3-epi-dihydrocinchonine(mp.- l l3l 17, as monohydratc from acetone).

EXAMPLE 18 Preparation of 7'-chlorocinchonine [7-chloro-a(S)-[5(R)-vinyl-4(S)-quinuclidin-2(R)-yl]-4- quinolinemethanol] and7-chlorocinchonidine [7-chloro-a(R)-l5(R)-vinyl-4(S)-]quinuclidin-2(S)-yl 4-quinolinemethanol]from 7-chlorodesoxycinchonine and 7'-chlorodesoxycinchonidine Thehydroxylation reaction was run in a 100 ml. three-neck flask connectedwith a gas burette and equipped with a gas outlet, an Erlenmeyer flaskattached by means of a piece of rubber tubing, and a magnetic stirrer. Asolution containing 0.164 g. of a mixture of 7'-ehlorodesoxycinchonineand 7'- eh1orodcsoxyeinchonidine in 10 ml. ofdimethylsulfoxide-t-butanol (4:1 was stirred in this flask in anatmosphere of dry oxygen at 20 for 10 minutes (no 0 uptake observed). Tothis solution was added 0.12 g. of potassium t-butoxide and the uptakeof oxygen was measured. 1 1.8 MI. of oxygen (about 1 molar equivalentwas consumed, and no further O -uptake was observed for 2 minutes.Whereupon, the reaction was quenched by the addition of 2 ml. of waterand a few drops of acetic acid. The resulting yellowish solution wasevaporated to dryness in vacuo (0.1 mm). The residue was dissolved indichloromethane and washed with 1N aqueous sodium hydroxide and water.dried over anhydrous sodium sulfate and evaporated. The residue wasseparated by preparative thin layer chromatography[chloroform-triethylaminc-methanol (:10:5)] to yield 7'-ch1oroeinchonineand 7-ch1orocinchonidine. 7-Chlorocinchonidine, crystallized fromacetoneether, had a melting point of 165169 (softens 145); [01],, 67 (c0.90, ethanol). 7-Chlorocinchoninc, crystallized from ethanol-acetone,had a melting point of 247250; [01],, 196 (c 0.88,ethanoldichloromethane, 4:1

EXAMPLE 19 [n a manner analogous to that of Examples 54 and iyll-4-quinolinemethanol, mp 196-l98, and its racemate, mp l02;6-methoxy-a(R)-[5(R)-ethyl-4(S)-quinuclidin-2(S)yll-4-quinolinemethanol, mp l72173, its antipode, mp 164166, andracemate, mp. 173l75; 6-methoxy-a(S)-[5(R)-ethyl-4(S)-quinuclidin-2(R)-yl]-4-quinolinemethanol, mp 169l70, its anti podc, mp'169170,. andracemate, mp 152154.5;6.7-methylenedioxy-a(R)-[5-vinyl-4(S)-quinuclidin-2(S)-yll-4-quinolinemcthanol racematc, mp v 224225;

6,7-methylenedioxy-a(S)-[5(R)-vinyl-4(S)-quinuclidin-2(R)-yl]-4'-quinolinemethanol racemate, mp 228229;6,7-methylcnedioxy-a( R 5( R )-ethyl-4(Squinuclidin-2(S)-yl-9-4-quinolincmethanol racemate, mp 232233;6,7-methylenedioxy-oz(S)-l5(R)-ethyl-4(S)- quinuclidin-2( R )-yl]-4-quinolinemethanol mate, mp 234-235;6,8-dichloro-oz(R)-[5(R)-ethyl-4(S)-quinuclidin-2(S)-yl]-4-quino1inemethanol raccmate (mp of dihydrochloride 226227);6,8-dichloro-a(S)-[5(R)-ethyl-4(S)-quinuclidin2(R)-yll-4-quinolinemethanol racemate, 172-173.

TZICC- Example 20 Tablet Formulation 22 Per Tabl t SuppositoryFormulation Per l.3 Gm. 6,7'-Dimcthoxydihydrocinehonine 2500 mg. pp yDicalcium Phosphate Dihydrate unmilled l75.00 mg.6'.7-Dintethnxydihydrocinchonidine 0.025 gm. Corn Starch 24.00 mg.Hydrogenated Coconut Oil 1.230 gm. Magnesium Stearatc L00 mg. CarnaubaWax 0.045 gm.

Total Weight 225.00 mg.

1 Procedure:

One-hundred-twenty-three Parts of hydrogenated coconut oil (Wecobee M E.F. Drew Co.. New York. Procedure: New York) and 4.5 parts of carnaubawax were melted 25 Parts of racemic 6,7'-dimethoxydihydrocin h in asuitable size glass lined container (stainless steel nine and 24 partsof corn starch were mixed together ay 8150 be mixed and COOI'Jd andpassed through a No. 00 screen in Model J Fitz- Parts of6',7-dimethoxy-dihydrocinchonidine. which mill with hammers forward.This premix was then had been reduced to a fine powder with no lumps,was mixed with l75 parts of dicalcium phosphate and oneadded and stirreduntil completely and uniformly dishalf part of magnesium stearate,passed through a No. persed. The mixture was poured into suppositorymolds lA screen in Model] Fitzmill with knives forward, and to yieldsuppositories having an individual weight of L3 slugged. The slugs werepassed through a No. 2A plate gms. The suppositories were cooled andremoved from in a Model D" Fitzmill at slow speed with knives formoldsand individually wrapped in wax paper for packward, and the remainingmagnesium stearate was aging added. The mixture was mixed andcompressed. w l i 1. A compound of the formula Example 2l N-II CapsuleFormulation I Per Capsule 6',7'-Dimethoxydihydrocinchonine 50 mg. {ICorn Starch, U.S.P. 150 mg. Talc. U.S.P. 10mg.

Total Weight 2H) mg. 011

Procedure: R

Fifty parts of racemie 6',7-dimethoxydihydrocinchonine were mixed with150 parts of com 40 w starch in a suitable mixer. The mixture wasfurther bicndcd y Passing through a pltzpifmck wherein m is 0, l or 2; Ris hydrogen, hydroxy, chloro, Machine with a No. 1A screen with knivesforward. ifl h methyl, mcthoxy ethyL pmpy] or The blended powder wasreturned to the mixer and I0 tylv or when m is 2, Rh taken together withan adjacent Parts Of talc were added and blended P Y- The R is alsomethylenedioxy; R is vinyl or ethyl; its antimixture was filled into N04 hard shell gelatin capsules podc or ruccmmc on a Parke Daviseapsulatmg machine. l l

1. A COMPOUND OF THE FORMUULA